Constitutive activity of signal transducer and activator of transcription 3 (STAT3) is observed in several human cancers, reflecting the importance of this transcription factor in the regulation of apoptosis and proliferation. STAT3 is required for te differentiation of Th17 cells, a subset of CD4+ helper T cells that produces the proinflammatory cytokine IL-17 and has been implicated in various inflammatory disorders. Studies have shown constitutive STAT3 activation and IL-17 production in T lymphocytes isolated from patients with cutaneous T cell lymphoma (CTCL), a disease in which malignant T cells migrate to the skin. These findings indicate that STAT3-driven Th17 cell differentiation may play a role in the pathogenesis of CTCL and other T cell malignancies. To examine the role of STAT3 in T cell transformation, a novel transgenic mouse model was developed in which CD4-Cre induces expression of a hyperactive mutant STAT3 (STAT3C) specifically in T cells. By six months of age, 100% of CD4-Cre R26STAT3Cstopfl/+ mice develop a lymphoproliferative disease highly reminiscent of CTCL. The mice have increased levels of Th17 cells in the lymph nodes and skin before visible skin pathology is present, suggesting that Th17-driven low-grade inflammation contributes to the development of the disease. The aims of this project are to examine the role of sustained chronic inflammation in the malignant transformation of T cells and to uncover reversible epigenetic changes in the STAT3 signaling pathway that accumulate during cellular transformation. An effective CTCL therapy approved for use in the clinic is the use of histone deacetylase (HDAC) inhibitors, suggesting that changes in acetylation may contribute to the pathogenesis of CTCL, and published observations indicate that HDAC inhibitors may modulate the transcriptional activity of STAT3. The described STAT3C mouse model of CTCL will be used to examine the contribution of STAT3-driven differentiation of proinflammatory Th17 cells to CTCL pathology and to investigate the effects of HDAC inhibitors on effector T cell differentiation in the context of this disease. The proposed experiments will reveal the role of a Th17-driven proinflammatory microenvironment in the development of CTCL and other lymphomas and will probe the chromatin changes that occur in T cells during transformation, potentially yielding novel drug targets for the treatment of lymphoid malignancies. PUBLIC HEALTH RELEVANCE: The proposed project has significant implications in the fields of immunology and cancer therapy, potentially improving the treatment options and quality of life for patients with lymphoma. The work is intended to examine the role of chronic inflammation in the development of the debilitating disease, cutaneous T cell lymphoma (CTCL). This research will examine the contribution of inflammatory T cells to CTCL pathology, as well as uncover reversible changes in immune cell signaling pathways that may serve as future targets for novel CTCL therapies and diagnostic strategies.